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US7671208B2 - Acetone solvate of phthaloyl amlodipine - Google Patents

Acetone solvate of phthaloyl amlodipine Download PDF

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Publication number
US7671208B2
US7671208B2 US11/756,607 US75660707A US7671208B2 US 7671208 B2 US7671208 B2 US 7671208B2 US 75660707 A US75660707 A US 75660707A US 7671208 B2 US7671208 B2 US 7671208B2
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methyl
ethyl
chlorophenyl
dihydro
pyridinedicarboxylate
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US20080242867A1 (en
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Ramón Berenguer Maimó
Jorge Medrano Rupérez
Juan Francisco Merodio Cabanillas
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Esteve Quimica SA
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Assigned to ESTEVE QUIMICA, S.A. reassignment ESTEVE QUIMICA, S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BERENGUER MAIMO, RAMON, MEDRANO RUPEREZ, JORGE, MERODIO CABANILLAS, JUAN FRANCISCO
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is directed to an acetone solvate of phthaloyl amlodipine, a process for its preparation and a method for the synthesis of amlodipine.
  • Amlodipine besylate also known as 2- ⁇ (2-aminoethoxy)-methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine ⁇ benzene sulfonate or 3-ethyl,5-methyl 2-((2-aminoethoxy)methyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate benzene sulfonate or 3-ethyl,5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate or 3-ethyl, 5-methyl 4-(2-chlorophenyl)-1,4-dihydro-6-methyl-2-(2-amino-ethoxymethyl)-3,5-pyridinedicarboxylate benzen
  • amlodipine besylate in which the key intermediate is phthaloyl amlodipine, also known as 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-(2-phtalimidoethoxy)-methyl-1,4-dihydropyridine or 3-ethyl, 5-methyl 4-(2-chlorophenyl)-1,4-dihydro-6-methyl-2-[(2-phthalimidoethoxy)methyl]-3,5-pyridinedicarboxylate.
  • phthaloyl amlodipine also known as 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-(2-phtalimidoethoxy)-methyl-1,4-dihydropyridine or 3-ethyl, 5-methyl 4-(2-chlorophenyl)-1,4-dihydro-6-methyl-2-[(2-phthalimidoethoxy)
  • phthaloyl amlodipine is obtained by condensation of phthalic anhydride with the corresponding free amine or condensation of 2-chlorobenzaldehyde, 4-[2-(phthalimido)ethoxy]acetoacetate and methyl 3-aminocrotonate. Purification of phthaloyl amlodipine is carried out by precipitation from acetic acid, followed by resuspension in methanol.
  • phthaloyl amlodipine is obtained by condensation between ethyl 3-amino-4-(2-phthalimidoetoxy)crotonate and methyl 2-(2-chlorobenzyliden)acetoacetate. Purification is carried out by recrystallization in methanol, ethanol, isopropanol, toluene or xylene.
  • phthaloyl amlodipine is purified by recrystallization in an organic solvent in the presence of acetic acid.
  • phthaloyl amlodipine is purified by a first recrystallizing in acetic acid, resuspending in methanol and finally by recrystallization from ethyl acetate.
  • U.S. Pat. No. 6,784,297 describes a process for the synthesis of amlodipine besylate starting from phthalic anhydride and comprising phthaloyl amlodipine as intermediate (step d)).
  • Phthaloyl amlodipine is subsequently purified in step e) in a two step sequence which comprises (i) dissolving it in an organic solvent in the ratio 1:2-1:5 w/v followed by (ii) precipitation by the addition of water at 35-60° C.
  • the solvent in step (i) is acetone.
  • the free phthaloyl amlodipine obtained is then transformed into its base and then into amlodipine besylate.
  • the purification methods of the prior art required complicated purification methods and are not capable of removing all the impurities to the levels required by applicable regulations.
  • FIG. 1 shows an X-ray powder diffractogram of the acetone solvate of the invention.
  • the abscissa axis shows the 2 ⁇ angles and the ordinate axis shows the intensity.
  • FIG. 2 shows an Infrared Spectrum of the acetone solvate of the invention.
  • the abscissa axis shows the frequency (cm ⁇ 1 ) and the ordinate axis shows the transmittance (% T).
  • the inventors have now surprisingly found that the provision of an acetone solvate of phthaloyl amlodipine provides an excellent method for the purification of phthaloyl amlodipine.
  • Recrystallization of phthaloyl amlodipine from acetone and further cooling provides an acetone solvate of phthaloyl amlodipine with high purity and yield, and without the need of using complicated work-up methods. Additionally, the acetone solvate of phthaloyl amlodipine shows a high degree of crystallinity, which makes it easy to manipulate and store.
  • the acetone solvate of phthaloyl amlodipine of the invention has excellent solubility and may be used to obtain amlodipine with high purity.
  • the present invention is directed to an acetone solvate of 3-ethyl, 5-methyl 4-(2-chlorophenyl)-1,4-dihydro-6-methyl-2-[(2-phthalimidoethoxy)methyl]-3,5-pyridinedicarboxylate.
  • the present invention is directed to a process for the synthesis of the acetone solvate of 3-ethyl, 5-methyl 4-(2-chlorophenyl)-1,4-dihydro-6-methyl-2-[(2-phthalimidoethoxy)methyl]-3,5-pyridinedicarboxylate, which comprises
  • the present invention is directed to a method for the synthesis of 3-ethyl, 5-methyl 2-((2-aminoethoxy)methyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate, its salts or solvates thereof, preferably its benzene sulfonate salt (amlodipine besylate), which comprises the use of an acetone solvent of 3-ethyl, 5-methyl 4-(2-chlorophenyl)-1,4-dihydro-6-methyl-2-[(2-phthalimidoethoxy)methyl]-3,5-pyridinedicarboxylate, as defined herein, as a starting material or as an intermediate.
  • the method of the invention does not comprise the addition of water. Instead, once the phthaloyl amlodipine is dissolved in acetone, the mixture is allowed to cool to a temperature comprised between ⁇ 10° C. and 20° C. The inventors have found that in this range of temperatures, the desired acetone solvate of phthaloyl amlodipine is readily obtained in good yields and high purity. According to a preferred embodiment, the mixture is cooled in step b) at a temperature comprised between ⁇ 5° C. and 5° C.
  • cooling in step b) is performed in two steps.
  • cooling in step b) is performed in two steps: a first cooling to a temperature comprised between above 5° C. and 20° C. and a second cooling to a temperature comprised between ⁇ 10° C. and 5° C.
  • said first cooling comprises a temperature between 7° C. and 15° C.
  • said first cooling comprises a temperature between 10° C. and 15° C.
  • said first cooling comprises a temperature between 8° C. and 12° C.
  • said second cooling comprises a temperature between 0° C. and 5° C.
  • the temperature to which phthaloyl amlodipine is heated or the concentration of phthaloyl amlodipine in step a) of the process is not critical. The only requirement is that phthaloyl amlodipine is dissolved. Therefore, the higher the temperature and/or the lower the concentration, the more readily phthaloyl amlodipine is dissolved.
  • the temperature in step a) is comprised between 30° C. and reflux. According to another preferred embodiment, the temperature in step a) is comprised between 40° C. and reflux.
  • the concentration of phthaloyl amolodipine in step a) is comprised between 0.02 and 0.3 g/ml, preferably between 0.04 and 0.2 g/ml.
  • the process of the invention comprises the additional step, between step a) and step b), of seeding the mixture with a crystal of an acetone solvate of 3-ethyl, 5-methyl 4-(2-chlorophenyl)-1,4-dihydro-6-methyl-2-[(2-phthalimidoethoxy)methyl]-3,5-pyridinedicarboxylate.
  • Such preferred embodiment comprises the following steps:
  • the process of the invention provides phthaloyl amlodipine with high purity, even with regard to impurities which are difficult to remove with other purification methods.
  • phthaloyl amlodipine is obtained in 70% yield and a purity of 98.6%.
  • Such process comprises the steps of a) condensation between (Z)-methyl 2-(2-chlorobenzylidene)-3-oxobutanoate and ethyl 3-amino-4-[2-(phthalimido)ethoxy]crotonate, and b) isolation of phthaloyl amlodipine.
  • One of the main impurities obtained is impurity HA
  • impurity HA 4-(2-Chloro-phenyl)-2,6-bis-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxymethyl]-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester or ethyl 2,6-bis[2-(phthalimidoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-3,5-pyridine dicarboxylate (named “impurity HA” for the purposes of the present invention).
  • impurity HA 4-(2-Chloro-phenyl)-2,6-bis-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxymethyl]-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester or ethyl 2,6-
  • the concentration of other impurities is also significantly reduced when forming the acetone solvate of phthaloyl amlodipine.
  • the acetone solvate of phthaloyl amlodipine obtainable by the process of the invention was characterized by X-ray powder diffractogram, thermogravimetric analysis (TG), differential scanning calorimetry (DSC) and infrared spectrum (IR).
  • the DSC measurements were carried out at a scan rate of 2° C./minute from 40° C. to 170° C. with a Mettler Toledo DSC822 e
  • Thermogravimetric analysis measurements were carried out at a scan rate of 5° C./minute from 25° C. to 200° C. with a Mettler Toledo TGA/STDA 851 e .
  • the acetone solvate of phthaloyl amlodipine shows an X-ray powder diffractogram having relevant peaks expressed as 20 angles at about 10.2, 12.1, 13.0, 13.9, 15.3, 17.5, 19.7, 20.6, 22.7, 23.5 and 24.4°.
  • a complete X-ray powder diffractogram is shown in FIG. 1 and a complete peak pattern is shown in Table 1 (peaks with an intensity below 5% are not shown).
  • the acetone solvate of phthaloyl amlodipine obtainable by the process of the invention shows an endothermal peak around 80° C., between 75° C. and 85° C.
  • the acetone solvate of phthaloyl amlodipine obtainable by the process of the invention shows a total weight loss of about 10.4%, between 7 and 12% w/w.
  • the theoretical acetone content of a sample is 9.7%.
  • the acetone solvate of phthaloyl amlodipine showed an IR spectrum having relevant peaks expressed in cm ⁇ 1 at about 3361, 2949, 1769, 1714, 1693, 1644, 1601, 1484, 1433, 1421, 1394, 1363, 1343, 1311, 1287, 1213, 1118, 1102, 1042, 1025, 727, 530 cm ⁇ 1 .
  • a complete IR is shown in FIG. 2 .
  • the acetone solvate of phthaloyl amlodipine is obtained in high yields and excellent purity.
  • the acetone solvate can then be readily liberated in order to obtain free phthaloyl amlodipine or it can be used directly.
  • an aspect of the present invention is a method for the synthesis of 3-ethyl, 5-methyl 2-((2-aminoethoxy)methyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate (amlodipine), its salts or solvates thereof which comprises the use of an acetone solvent of 3-ethyl, 5-methyl 4-(2-chlorophenyl)-1,4-dihydro-6-methyl-2-[(2-phthalimidoethoxy)methyl]-3,5-pyridinedicarboxylate (acetone solvate of phthaloyl amlodipine) as defined above as a starting material or as intermediate
  • such method is for the synthesis of 3-ethyl, 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate.
  • the acetone solvate of phthaloyl amlodipine may be used as the starting material in the synthesis of amlodipine following any of the methods described in the prior art.
  • amlodipine besylate may be obtained using the acetone solvate of phthaloyl amlodipine by the method described in U.S. Pat. No. 6,784,297.
  • Examples 2 and 3 illustrate the method of synthesis of the acetone solvate of phthaloyl amlodipine.
  • Phthaloyl amlodipine (10 g, purity: 95.4%) was dissolved in 50 ml of acetone under reflux. Once solution was complete, it was cooled slowly to 15/10° C. Then the solution was cooled to 5/0° C. and the solid was filtered off and washed with cold acetone. The product was dried under vacuum. Yield of Phthaloyl amlodipine acetone solvate: 9.2 g. Purity: 98.9%.
  • Phthaloyl amlodipine (10 g, purity: 98.6%) was dissolved in 60 ml of acetone under reflux. Then the solution is cooled to 45/30° C. and seeded with Phthaloyl amlodipine acetone solvate to allow precipitation. The suspension was then cooled to 5/0° C., filtered off and washed with cold acetone. The solid was dried under vacuum. Yield of Phthaloyl amlodipine acetone solvate: 10.5 g. Purity: 99.9%.
  • the following examples 4 to 6 further illustrate the method of synthesis of the acetone solvate of phthaloyl amlodipine.
  • the comparative examples correspond to examples 1 to 4 of U.S. Pat. No. 6,784,297, respectively, and have been prepared for comparative purposes. As shown in examples 7 to 10 below, the process according to U.S. Pat. No. 6,784,297 does not provide the acetone solvate of phthaloyl amlodipine.
  • the levels of impurity HA have been measured in examples 4 to 10.
  • the provision of the acetone solvate of phthaloyl amlodipine according to the present invention yields a final product with higher levels of purity compared to the method disclosed in U.S. Pat. No. 6,784,297. A similar trend has been observed with other impurities.
  • Phthaloyl amlodipine (10 g, purity: 95.4%; 1.06% of impurity HA) was dissolved in 50 ml of acetone under reflux. Once solution was complete, it was cooled slowly to 15/10° C. Then the solution was cooled to 5/0° C. and the solid was filtered off and washed with cold acetone.
  • the product was dried under vacuum at room temperature.
  • Phthaloyl amlodipine (10 g, purity: 92.8%; 1.90% of impurity HA) was dissolved in 173 ml of acetone at 32° C. Once solution was complete, it was cooled to 12/8° C. until precipitation. Then the slurry was cooled to 5/0° C. and the solid was filtered off and washed with cold acetone.
  • the product was dried under vacuum at room temperature.
  • Phthaloyl amlodipine (10 g, purity: 98.6%; 0.86% of impurity HA) was dissolved in 60 ml of acetone under reflux. Then the solution is cooled to 45/30° C. and seeded with Phthaloyl amlodipine acetone solvate to allow precipitation. The suspension was then cooled to 5/0° C. and water (5 ml) was added. The solid was filtered off, washed with acetone and dried under vacuum at room temperature.
  • Purity 99.94%; 0.01% of impurity HA.
  • Phthaloyl amlodipine (10 g, purity: 98.6%; 0.86% of impurity HA) was dissolved in 35 ml of acetone at reflux and cooled to 45° C. Water (10 ml) was slowly added to precipitate the product which was cooled to 5/0° C. and dried under vacuum at room temperature.
  • Phthaloyl amlodipine (10 g, purity: 98.6%; 0.86% of impurity HA) was dissolved in 50 ml of acetone at 45° C. and 14 ml of water was slowly added to precipitate the product which was cooled to 5/0° C. and dried under vacuum.
  • Phthaloyl amlodipine (10 g, purity: 98.6%; 0.86% of impurity HA) was slurried in 25 ml of acetone, heated to reflux for 15 min and cooled to 45° C. Water (9 ml) was slowly added to precipitate the product which was cooled to 5/0° C. and dried under vacuum at room temperature.
  • Phthaloyl amlodipine (10 g, purity: 98.6%; 0.86% of impurity HA) was dissolved in 50 ml of acetone at 45° C. and 15 ml of water was slowly added to precipitate the product which was cooled to 5/0° C. and dried under vacuum at room temperature.

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  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US11/756,607 2007-03-30 2007-05-31 Acetone solvate of phthaloyl amlodipine Expired - Fee Related US7671208B2 (en)

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EPEP07380086.4 2007-03-30
EP07380086A EP1975167A1 (fr) 2007-03-30 2007-03-30 Solvate d'acétone de phtaloyl amlodipine
EP07380086 2007-03-30

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EP (2) EP1975167A1 (fr)
JP (1) JP5323808B2 (fr)
KR (1) KR20100015983A (fr)
CN (1) CN101675039A (fr)
AT (1) ATE471317T1 (fr)
AU (1) AU2008234885A1 (fr)
CA (1) CA2682535A1 (fr)
DE (1) DE602008001560D1 (fr)
ES (1) ES2347735T3 (fr)
IL (1) IL201229A (fr)
MX (1) MX2009010525A (fr)
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RU (1) RU2009140050A (fr)
SI (1) SI2132195T1 (fr)
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JP2010100562A (ja) * 2008-10-23 2010-05-06 Daito Kk アムロジピン製造中間体の精製方法
JP5952748B2 (ja) * 2013-01-25 2016-07-13 東和薬品株式会社 フタロイルアムロジピンの新規結晶形態およびそれを用いる高純度なアムロジピンベシル酸塩の製造方法

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US4572908A (en) 1982-12-21 1986-02-25 Pfizer Inc. Dihydropyridines
WO2000047560A2 (fr) 1999-02-15 2000-08-17 EGIS Gyógyszergyár Rt. Procede de preparation d'esters d'acide asymetrique 1,4-dihydro-pyridine-dicarboxylique
RU2161156C1 (ru) 1999-06-01 2000-12-27 Джи.Б.Кемикалс Энд Фармасьютикалс Лтд Способ получения 3-этил-5-метиловый эфир 2-[2-(n-фталимидо)-этоксиметил]-4-(2-хлорфенил)-1,4-дигидро-6-метил-3,5- пиридиндикарбоновой кислоты
WO2001002360A1 (fr) 1999-07-05 2001-01-11 Richter Gedeon Vegyészeti Gyár Rt. Procede de preparation de benzenesulphonate d'amlodipine
HRP20000490A2 (en) 2000-07-21 2002-02-28 Belupo Lijekovi I Kozmetika D Process for the preparation of amlodipine besilate
WO2002053135A1 (fr) 2000-12-29 2002-07-11 Pfizer Limited Base libre d'amlodipine
DE20201878U1 (de) 2002-02-07 2002-07-11 Bioorganics B.V., Nijmegen Freie Amlodipinbase
ES2177409A1 (es) 2000-08-02 2002-12-01 Liconsa Liberacion Controlada Procedimiento para la obtencion de 1,4-dihidropiridinas substituida utiles para el tratamiento de la hipertension.
WO2004058711A1 (fr) 2002-12-30 2004-07-15 Eos Eczacibasi Ozgun Kimyasal Urunler Sanayi Ve Ticaret A.S. Isolation de derive de dihydropyridine et sels de preparation de celui-ci
WO2005023769A1 (fr) 2003-09-04 2005-03-17 Cipla Limited Procede pour l'elaboration de sels d'amlodipine
WO2006003672A1 (fr) 2004-07-02 2006-01-12 Matrix Laboratories Ltd Procede de preparation d'amlodipine pure

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DK161312C (da) * 1982-03-11 1991-12-09 Pfizer Analogifremgangsmaade til fremstilling af 2-aminoalkoxymethyl-4-phenyl-6-methyl-1,4-dihydropyridin-3,5-dicarboxylsyreestere eller syreadditionssalte deraf samt phthalimidoderivater til anvendelse som udgangsmateriale ved fremgangsmaaden
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WO2000047560A2 (fr) 1999-02-15 2000-08-17 EGIS Gyógyszergyár Rt. Procede de preparation d'esters d'acide asymetrique 1,4-dihydro-pyridine-dicarboxylique
RU2161156C1 (ru) 1999-06-01 2000-12-27 Джи.Б.Кемикалс Энд Фармасьютикалс Лтд Способ получения 3-этил-5-метиловый эфир 2-[2-(n-фталимидо)-этоксиметил]-4-(2-хлорфенил)-1,4-дигидро-6-метил-3,5- пиридиндикарбоновой кислоты
WO2001002360A1 (fr) 1999-07-05 2001-01-11 Richter Gedeon Vegyészeti Gyár Rt. Procede de preparation de benzenesulphonate d'amlodipine
HRP20000490A2 (en) 2000-07-21 2002-02-28 Belupo Lijekovi I Kozmetika D Process for the preparation of amlodipine besilate
ES2177409A1 (es) 2000-08-02 2002-12-01 Liconsa Liberacion Controlada Procedimiento para la obtencion de 1,4-dihidropiridinas substituida utiles para el tratamiento de la hipertension.
WO2002053135A1 (fr) 2000-12-29 2002-07-11 Pfizer Limited Base libre d'amlodipine
WO2002053535A2 (fr) 2000-12-29 2002-07-11 Bioorganics B.V. Procede de fabrication de l'amlodipine, derives de l'amlodipine et precurseurs associes
DE20201878U1 (de) 2002-02-07 2002-07-11 Bioorganics B.V., Nijmegen Freie Amlodipinbase
WO2004058711A1 (fr) 2002-12-30 2004-07-15 Eos Eczacibasi Ozgun Kimyasal Urunler Sanayi Ve Ticaret A.S. Isolation de derive de dihydropyridine et sels de preparation de celui-ci
WO2005023769A1 (fr) 2003-09-04 2005-03-17 Cipla Limited Procede pour l'elaboration de sels d'amlodipine
WO2006003672A1 (fr) 2004-07-02 2006-01-12 Matrix Laboratories Ltd Procede de preparation d'amlodipine pure

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English Language Summaries of Foreign Patent Documents RU2161156, ES2177409, HR20000490, and DE20201878.
Yathirajan, H.S., et al., "Phthaloyl amlodipine", "Acta Cryst.", Jan. 2005, pp. o175-o175, vol. E61, No. Pt. 1.

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EP1975167A1 (fr) 2008-10-01
SI2132195T1 (sl) 2010-08-31
IL201229A0 (en) 2010-05-31
ES2347735T3 (es) 2010-11-03
CN101675039A (zh) 2010-03-17
ATE471317T1 (de) 2010-07-15
JP2010523521A (ja) 2010-07-15
AU2008234885A1 (en) 2008-10-09
KR20100015983A (ko) 2010-02-12
EP2132195B1 (fr) 2010-06-16
US20080242867A1 (en) 2008-10-02
EP2132195A1 (fr) 2009-12-16
DE602008001560D1 (de) 2010-07-29
IL201229A (en) 2013-05-30
JP5323808B2 (ja) 2013-10-23
WO2008119759A1 (fr) 2008-10-09
RU2009140050A (ru) 2011-05-10

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